CN107224587A - A kind of protoporphyrin zinc-aluminum hydrotalcite compound and its preparation method and application - Google Patents
A kind of protoporphyrin zinc-aluminum hydrotalcite compound and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of protoporphyrin zinc-aluminum hydrotalcite compound and its preparation method and application, belong to Inorganic whisker functional material and medicine sustained and controlled release field.Described protoporphyrin zinc-aluminium water complex is made up of zinc-aluminum hydrotalcite and protoporphyrin, there is electrostatic interaction between the two, and protoporphyrin is adsorbed in zinc-aluminum hydrotalcite surface；The weight content of protoporphyrin is 0.01 50% in compound.The present invention protoporphyrin zinc-aluminium neatly compound under stomach pH environment, can slowly discharge protoporphyrin, can as protoporphyrin sustained release preparation.After protoporphyrin and zinc-aluminum hydrotalcite formation compound, can overcome the hydrochloric acid in gastric juice of protoporphyrin stimulates side effect, it is possible to the phototoxicity of protoporphyrin is effectively reduced, with significant clinical value.
Description
Technical field
The invention belongs to inorganic-organic composite function material and medicine sustained and controlled release field, and in particular to one kind has sustained release
The protoporphyrin of effect-zinc-aluminum hydrotalcite compound and preparation method and application.
Background technology
Protoporphyrin disodium (Protoporphyrinsodium, Prolmon, NAPP), entitled 3,7,12, the 17- tetramethyl of chemistry-
8,13- divinyl -2,18- porphines dipropionic acids, also known as Protoporphyrin Disodium, are that obtained former porphin is obtained through refining from healthy ox, pig blood
The water-soluble sodium salt of quinoline (Protoporphyrin IX).Protoporphyrin disodium is a kind of conventional hepatoprotective agent, with promotion cell tissue
Breathing, improves protein and glycometabolism, and anticomplement combination etc. is acted on.The treatment of Various Types of Hepatitis is clinically used for, disease can be made
Shape improves, and liver is swollen to be reduced, the target improvement such as aminopherase, turbidity test, icterus index.
Hydrotalcite, also known as layered di-hydroxyl composite metal oxidate (Layered Double Hydroxide), are tools
There is the inorganic two-dimensional material of unique layer structure.Its composition of hydrotalcite can be expressed as follows：
[(M2+)1-x(M3+)x(OH)2]x+(An-)x/n·mH2O
In above formula, bivalent metal ion M2+Can be Mg2+、Ni2+、Co2+、Zn2+、Cu2+Deng；Trivalent metal ion M3+Can be with
It is Al3+、Fe3+、Cr3+Deng；An-It is the tradable anion of interlayer, including inorganic anion (CO3 2-、NO3 -、SO4 2-Or Cl-), have
Machine anion and heteropolyanion；X values are 0.16~0.33, corresponding to bivalent cation M2+With Tricationic M3+Ratio
For 4：1~2：1；M represents the number of the hydrone of interlayer.Used in the present invention is zinc-aluminum hydrotalcite.Zinc-aluminum hydrotalcite is in first
Positively charged two dimensional surface nanometer sheet can be stripped into acid amides.
Contain COO in protoporphyrin disodium molecular structure-, it is ionic compound, protonation under one's belt is converted into molecule chemical combination
It can be just absorbed by the body after thing.But weak acidic drug has stronger excitant, such as aspirin, brufen to stomach,
Protoporphyrin disodium also there is hydrochloric acid in gastric juice to stimulate side effect.
The content of the invention
It is an object of the invention to provide a kind of protoporphyrin-zinc-aluminum hydrotalcite compound and its preparation method and application.It is former
Porphyrin-hydrotalcite complex can be not only able to overcome the hydrochloric acid in gastric juice of protoporphyrin as protoporphyrin oral slow-releasing preparation, the sustained release preparation
Stimulate side effect, it is possible to which effectively former porphin reduces quinoline phototoxicity.
To achieve the above object, the present invention is adopted the following technical scheme that：
Protoporphyrin provided by the present invention-zinc-aluminum hydrotalcite compound is made up of zinc-aluminum hydrotalcite and protoporphyrin, both it
Between there is electrostatic interaction, protoporphyrin absorption zinc-aluminum hydrotalcite surface；The weight content of protoporphyrin is 0.01-50%.Neatly
Stone (including its analog), is layered di-hydroxyl composite metal oxidate, is the inorganic two-dimensional material with layer structure.This hair
The bright hydrotalcite used is zinc-aluminum hydrotalcite, and interlayer anion is NO3 -, consisting of：[Zn1-xAlx(OH)2]x+
(NO3 -)x·mH2O, x value are 0.16-0.33, and m values are 0.5-2.
Protoporphyrin (Protoporphyrin IX), is the metalloporphyrin complex with anion substituent.Protoporphyrin and its water
Dissolubility sodium salt protoporphyrin disodium structure is as follows：
The preparation method of protoporphyrin of the present invention-zinc-aluminum hydrotalcite compound, comprises the following steps：
(1) zinc-aluminum hydrotalcite is prepared：Prepare zinc ion and aluminum ions mixing salt solution, alkali lye and containing nitrate anion from
The aqueous solution of son；Zinc ion and aluminum ions mol ratio are 2 in the mixing salt solution:1, hydroxide ion in the alkali lye
The amount of material is 2 times of the amount sum of zinc ion and aluminium ion material；
At 15-30 DEG C of temperature, nitrogen protection and stirring condition, above-mentioned mixing salt solution and alkali lye are added dropwise to simultaneously and contained
Have in the aqueous solution of nitrate ion, be warming up to 50-70 DEG C after completion of dropping, aging 1-3h, aging, which is finished, pours into reaction solution
In high-temperature high-pressure reaction kettle, hydro-thermal reaction 6-12h obtains crude product at 110-130 DEG C, and the crude product is by centrifuging, washing
Wash, dry after, obtain nitrate anion type zinc-aluminum hydrotalcite；
(2) peel off zinc-aluminum hydrotalcite and obtain nanometer sheet gel：Above-mentioned nitrate anion type zinc-aluminum hydrotalcite is added into formamide molten
In liquid, ultrasound is swelled 15-35min and obtains mixed liquor, and then by mixed liquor, (control mixeding liquid temperature is no more than 30 in ice bath again
DEG C) with ultrasonic grinder strength ultrasound 15-35min, gained clear solution standing after form colourless zinc-aluminum hydrotalcite nanometer sheet
Gel；
(3) protoporphyrin-zinc-aluminum hydrotalcite compound is prepared：Protoporphyrin disodium is dissolved in absolute ethyl alcohol, adjusted with NaOH solution
Section system apparent pH is 10, obtains solution A；
The zinc-aluminum hydrotalcite nanometer sheet gel that step (2) is obtained is dissolved in formamide, obtains solution B；
At 15 DEG C -30 DEG C of temperature, nitrogen protection, solution A is added drop-wise in solution B, 40-50 DEG C is warming up to, continues to stir
Reaction 1-2h is mixed, after product is by centrifugation, washing, drying process, protoporphyrin-zinc-aluminum hydrotalcite compound is produced.
Further, the ratio of the step (2), nitrate anion type zinc-aluminum hydrotalcite and formamide is 1000 milligrams: 40-60 milli
Rise.
The volume ratio of zinc-aluminum hydrotalcite nanometer sheet gel and formamide is 1: 3 in the step (3), solution B.
Protoporphyrin prepared by the present invention-granularity of zinc-aluminum hydrotalcite compound in aqueous is 180-300nm.
The present invention uses above technical scheme, utilizes the electrostatic interaction between protoporphyrin anion and hydrotalcite, structure
A kind of novel protoporphyrin-hydrotalcite complex has been built, it is found that protoporphyrin-hydrotalcite complex can inhale as protoporphyrin in stomach
The sustained release preparation of receipts, the sustained release preparation can not only overcome the hydrochloric acid in gastric juice of protoporphyrin to stimulate side effect, it is possible to be effectively reduced its light
Toxicity, with significant clinical value.
The remarkable advantage of the present invention is：
(1) prices of raw materials for preparing zinc-aluminum hydrotalcite are cheap, abundance.
(2) preparation process is easy to operate, and reappearance is high.Zinc-aluminum hydrotalcite and its gel in formamide obtained by stripping,
Property is stable, is easy to storage, is conducive to being prepared on a large scale in the industrial production.
(3) hydrotalcite-based compound is usually constructed with the specific surface area (5-20m of very little2/g).The present invention is by zinc-aluminum hydrotalcite
Peeled off into formamide positively charged, have the nanometer sheet of two dimensional surface attribute, it can be effectively improved than surface, Jin Erti
The contact area of high zinc-aluminum hydrotalcite and protoporphyrin, enables zinc-aluminum hydrotalcite is more more firmly to carry protoporphyrin.
(4) formamide is virose, there is larger harm to organism.The present invention passes through the zinc in NAPP and formamide
Aluminum hydrotalcite nano piece electrostatic attraction interacts, sol system of the destruction hydrotalcite nano piece in formamide, so that multiple
Compound precipitates, and the formamide remained in precipitation, which is then washed with water, just can thoroughly remove formamide.
(5) zinc-aluminum hydrotalcite resolves into inorganic salts, oral safety non-toxic by hydrochloric acid in gastric juice under one's belt.
(6) protoporphyrin-hydrotalcite complex can not only overcome original as protoporphyrin oral slow-releasing preparation, the sustained release preparation
The hydrochloric acid in gastric juice of porphyrin stimulates side effect, it is possible to be effectively reduced the phototoxicity of protoporphyrin.
Brief description of the drawings
Fig. 1 is nitrate anion type zinc-aluminum hydrotalcite (Zn2-Al-NO3- LDHs) X-ray diffraction (XRD) spectrogram.
Fig. 2 is gel (Zn obtained by stripping of the zinc-aluminum hydrotalcite in formamide2- Al-LDHs-exfoliation) X penetrate
Line diffraction (XRD) spectrogram.
Fig. 3 is protoporphyrin-zinc-aluminum hydrotalcite compound (PPIX-LDHs), protoporphyrin disodium (NAPP), zinc-aluminum hydrotalcite
(Zn2-Al-NO3- LDHs) infrared spectrum.
Fig. 4 be protoporphyrin disodium (NAPP) and its with the compound (PPIX-LDHs) of zinc-aluminum hydrotalcite in dimethyl sulfoxide (DMSO)
(DMSO) ultraviolet-visible absorption spectroscopy figure in (NAPP concentration is 2.3 μM, and PPIX-LDHs is 2.35 μM).
Fig. 5 be protoporphyrin disodium (NAPP) and its with the compound (PPIX-LDHs) of zinc-aluminum hydrotalcite in dimethyl sulfoxide (DMSO)
(DMSO) fluorescence spectra in (NAPP concentration is 2.3 μM, and PPIX-LDHs concentration is 2.35 μM).
Fig. 6 be protoporphyrin-zinc-aluminum hydrotalcite compound (PPIX-LDHs) in pH=2.4 cushioning liquid, PPIX is at any time
Between release profiles.
Fig. 7 is protoporphyrin-zinc-aluminum hydrotalcite compound (PPIX-LDHs), the protoporphyrin disodium of same concentrations (6.5 μM)
(NAPP), zinc-aluminum hydrotalcite (Zn2-Al-NO3- LDHs) make chemical probe 1,3 diphenyl isobenzofuran (DPBF) under light illumination
The curve of degraded.
Embodiment
The preparation method of protoporphyrin of the present invention-zinc-aluminum hydrotalcite compound comprises the following steps：
(1) zinc-aluminum hydrotalcite is prepared：Prepare zinc ion and aluminum ions mixing salt solution, alkali lye and containing nitrate anion from
The aqueous solution of son；Zinc ion and aluminum ions mol ratio are 2 in the mixing salt solution:1, hydroxide ion in the alkali lye
The amount of material is 2 times of the amount sum of zinc ion and aluminium ion material；
In temperature 15-30, under DEG C nitrogen protection and stirring condition, above-mentioned mixing salt solution and alkali lye are added dropwise to simultaneously and contained
Have in the aqueous solution of nitrate ion, 50-70 is warming up to after completion of dropping, DEG C aging 1-3h, aging, which is finished, pours into reaction solution
In high-temperature high-pressure reaction kettle, hydro-thermal reaction 6-12h obtains crude product at 110-130 DEG C, and the crude product is by centrifuging, washing
Wash, dry after, obtain nitrate anion type zinc-aluminum hydrotalcite；
(2) peel off zinc-aluminum hydrotalcite and obtain nanometer sheet gel：Above-mentioned nitrate anion type zinc-aluminum hydrotalcite is added into formamide molten
In liquid (1000 milligrams of zinc-aluminum hydrotalcites need 40-60 milliliters of formamide), ultrasound is swelled 15-35min and obtains mixed liquor, Ran Houzai
(mixeding liquid temperature is controlled to be no more than 30 DEG C) with ultrasonic grinder strength ultrasound 15-35min, gained in ice bath mixed liquor
Clear solution forms colourless zinc-aluminum hydrotalcite nanometer sheet gel after standing；
(3) protoporphyrin-zinc-aluminum hydrotalcite compound is prepared：Protoporphyrin disodium is dissolved in absolute ethyl alcohol, adjusted with NaOH solution
Section system apparent pH is 10, obtains solution A；
The zinc-aluminum hydrotalcite nanometer sheet gel that step (2) is obtained is dissolved in the formamide of its 3 times of volumes, obtains solution B；
At 15 DEG C -30 DEG C of temperature, nitrogen protection, solution A is added drop-wise in solution B, 40-50 DEG C is warming up to, continues to stir
Reaction 1-2h is mixed, after product is by centrifugation, washing, drying process, protoporphyrin-zinc-aluminum hydrotalcite compound is produced.
The composition of zinc-aluminum hydrotalcite prepared by step (1) is expressed as：[Zn1-xAlx(OH)2]x+(NO3 -)x·mH2O, x value is
0.16-0.33, m value are that the weight content of protoporphyrin in 0.5-2, gained protoporphyrin-zinc-aluminum hydrotalcite compound is 0.01-
50%.The granularity of compound in aqueous is 180-300nm.
The surface potential for measuring protoporphyrin-zinc-aluminum hydrotalcite compound is 30-40mv, is overcome because protoporphyrin is in faintly acid
And the deficiency with hydrochloric acid in gastric juice side effect.
Sustained release experiment under gastric juice environmental condition shows that protoporphyrin-zinc-aluminum hydrotalcite compound can be slow at 1 hour or so
Protoporphyrin is disengaged, protoporphyrin-zinc-aluminum hydrotalcite compound can improve the stomach of protoporphyrin as effective protoporphyrin sustained release preparation
Sour side effect.
Photosensitive toxicity test shows that protoporphyrin-zinc-aluminum hydrotalcite compound can completely inhibit the photosensitive toxicity of protoporphyrin.
For the further open rather than limitation present invention, below in conjunction with example, the present invention is further illustrated.
Embodiment 1
(1) synthesis of nitrate anion type zinc-aluminum hydrotalcite：Weigh 1.19gZn (NO3)2·6H2O (4mmol), 0.75gAl
(NO3)3·9H2O (2mmol), is dissolved in 40ml and boils in the water for removing carbon dioxide, be made into mixing salt solution.Weigh 0.486g
(12mmol) NaOH, is dissolved in 40ml and goes in carbon dioxide water, be made into alkali lye.Weigh 1g anhydrous Nas NO3, it is dissolved in 20ml and goes titanium dioxide
In carbon water, the aqueous solution is made into.Normal temperature (15 DEG C -30 DEG C), it is under conditions of nitrogen protection and strength mechanical agitation, salt-mixture is molten
Liquid is slowly dropped into NaNO with alkali lye3In the aqueous solution, strict control drop speed makes the rate of addition complete one of mixing salt solution and alkali lye
Cause.After completion of dropping, reacting liquid temperature is improved to 50-70 DEG C, aging 1-3h.Aging is finished, and reaction solution is poured into HTHP
In reactor, the hydro-thermal 6-12h at 120 DEG C, then carbon dioxide washing three times is spent, wash salinity off.Brilliant white is deposited in 40
It is dried in vacuo at DEG C, obtained white solid as zinc-aluminum hydrotalcite.Finally by gained white solid mortar grinder to fine powder
Shape, isolation air, which is stored in, to be placed with the drier of discoloration silica gel.
(2) stripping of the zinc-aluminum hydrotalcite in formamide：Weigh the zinc-aluminum hydrotalcite 0.4g that step (1) obtains and pour into glass
In test tube, 20-30ml formamides are added, ultrasound 15-35min in numerical control ultrasonic cleaner is put into, then again places test tube
In ice bath, control temperature is no more than 30, DEG C with cell supersonic wave pulverizer strength ultrasound 15-35min, and gained clear solution is quiet
Postpone, form colourless zinc-aluminum hydrotalcite nanometer sheet gel.
(3) preparation of protoporphyrin-zinc-aluminum hydrotalcite compound：Weigh 12.4mg protoporphyrin disodiums and be dissolved in 20ml absolute ethyl alcohols
In, and pH=10 is seen with 0.01mol/L NaOH solution mileometer adjustment, obtain the ethanol solution of protoporphyrin.Step is taken with liquid-transfering gun
Suddenly the zinc-aluminum hydrotalcite nanometer sheet gel 5ml (gel strength 20mg/ml) that (2) are prepared, is dissolved in 15ml formamides, obtains zinc
The formamide solution of aluminum hydrotalcite, pours into the footpath flasks of 100ml tri- by the formamide solution of zinc-aluminum hydrotalcite, is fixed on magnetic force
In the thermostatical oil bath of agitating device.The ethanol solution of protoporphyrin is poured into 50ml constant pressure funnels.Normal temperature (15
DEG C -30 DEG C), protected in nitrogen and under magnetic stirring, the ethanol solution liquid of protoporphyrin is slowly dropped to zinc-aluminium neatly
In the formamide solution of stone.After dripping off, mixeding liquid temperature is promoted to 40-50 DEG C, 1-2h is reacted.Reaction is finished, by gained
Brownish red slurry liquid, is cleaned by supercentrifuge with pure water, until supernatant is colourless.By sediment in 40 DEG C of vacuum drying
12h, obtained brown-red solid is protoporphyrin-zinc-aluminum hydrotalcite compound.Finally by the brown-red solid mortar grinder
To fine-powdered, it is placed in brown drier and is kept in dark place.
Embodiment 2
The X-ray of zinc-aluminum hydrotalcite nanometer sheet gel is spread out after the present embodiment tests nitrate anion type zinc-aluminum hydrotalcite and peeled off
Peak is penetrated, Fig. 1 and 2 is seen respectively.As can be seen from Figure 1, obtained material is typical zinc-aluminum hydrotalcite.
According to document《Chemical Communications》,2014,50(70):10130-2, it is known that if hydrotalcite
Monolithic successfully is stripped into formamide, X-ray diffraction is done to the gel formed, hydrotalcite characteristic peak (003),
(006) it can disappear, and the one wide and weaker diffraction maximum of intensity occurs equal to 25 ° or so in 2 θ.The gel of formation is equal
Even is applied on slide, ensures that gel face is smooth as far as possible, does XRD signs, acquired results are shown in Fig. 2, complete with document report
Unanimously, illustrate to have obtained zinc aluminum hydrotalcite nano piece.The test parameter that XRD is characterized is all：Cu targets, K alpha rays, scanning speed
Spend 10 °/min.
Embodiment 3
Anionic group-the COO that protoporphyrin disodium NAPP contains-It is weak acid radical ion.If the pH value of solution is too low, largely
- COO-COOH will be converted into.Even if in neutral solution ,-COO-Also can occur hydrolysis, be partially converted into-COOH.Must
It must ensure there is enough-COO-, could occur electrostatic adsorption with positively charged zinc-aluminum hydrotalcite nanometer sheet, and prepare
Compound.In order to keep-COO-Degree of dissociation, solution must be tuned into meta-alkalescence, but if solution alkaline is too strong, zinc-aluminum hydrotalcite
(Zn2-Al-NO3 -- LDHs) structure can be destroyed.
In order to explore influence of the solution ph to zinc-aluminum hydrotalcite-porphyrin complex synthesis, respectively by NAPP absolute ethyl alcohols
The apparent pH of solution is transferred to 9,10,11, and three groups of parallel laboratory tests are carried out with zinc-aluminum hydrotalcite nanometer sheet.If NAPP absolute ethyl alcohols
The apparent pH of solution is 9, and reaction solution obtained by centrifugation (centrifugal speed 15000r/min) can not be precipitated, if using laser
Pen irradiation reaction mixture, has obvious Tyndall effect, illustrates that-COOH is just without enough degrees of dissociation in NAPP, it is impossible to
The colloidal dispersion that electrostatic attraction destroys hydrotalcite nano piece effectively occurs with hydrotalcite nano piece.If NAPP absolute ethyl alcohols are molten
The apparent pH of liquid is 11, will react more the red-brown powder that obtains do X-ray diffraction, almost there is no XRD diffraction maximums, illustrate the powder
Last substantially no crystal structure, hydrotalcite has been destroyed.Only when the apparent pH of NAPP ethanol solutions is 10,
Both it can guarantee that-COOH had enough degrees of dissociation in PPIX, the distinctive layered crystal structure of hydrotalcite can be protected not to be damaged again.
Embodiment 4
Fig. 3 is protoporphyrin-zinc-aluminum hydrotalcite compound (PPIX-LDHs), protoporphyrin (NAPP), zinc-aluminum hydrotalcite (Zn2-
Al-NO3- LDHs) the FT-IR spectrograms made of powder and anhydrous K Br tablettings.In 3400cm-1The wide and strong peak that place occurs is
The characteristic peak of-OH stretching vibrations on hydrotalcite layers hydrone or laminate, NAPP is sodium salt, therefore without this peak.In 1383cm-1Place
It is NO3 -Characteristic absorption peak.In 700cm-1And 616cm-1The absworption peak of position belongs to Zn-O and Al-O lattice vibration.
424cm-1It is the characteristic absorption peak of hydrotalcite-based compound.1617cm on NAPP-1And 1563cm-1Absworption peak is respectively from C=
Stretching vibration on O and aromatic rings.
This infrared spectrum is analyzed, it is observed that：(1) PPIX-LDHs is in 1383cm-1Locate NO3 -Characteristic absorption peak ratio
Zn2-Al-NO3- LDHs is weak；(2) do not have C=O characteristic absorption peak on PPIX-LDHs, it is only remaining to be located at 1580cm-1Place
The stretching vibration peak of aromatic rings；(3) PPIX-LDHs and Zn2-Al-NO3- LDHs has in 424cm-1Locate hydrotalcite chemical combination
The characteristic peak of thing.We can draw to draw a conclusion：NO on NAPP substitutions part LDHs3 -, its characteristic absorption peak is died down,
- OH on C=O and LDHs on NAPP produces hydrogen bond, C=O stretching vibrations on PPIX-LDHs is disappeared, NAPP is successful
It has been compound on LDHs.
Embodiment 5
In the DMSO that a certain amount of PPIX-LDHs to 2ml is added dropwise, UV-vis spectrum are surveyed.The hydrochloric acid for adding 20 μ l 1mol/L will
Hydrotalcite is destroyed, and adds 20 μ l 1mol/L sodium hydroxide, then surveys UV-vis spectrum, and first acid adding is destruction hydrotalcite structure,
Again plus alkali is that the PPIX that will be discharged is converted into sodium salt NAPP.Accompanying drawing 4 is visible, PPIX after PPIX-LDHs is discharged, its
Any change will not occur for ultraviolet-visible absorption spectroscopy, illustrate that any change will not occur for its property.With same procedure, do glimmering
Light spectrum experiment, can obtain analog result, see, Fig. 5.With reference to Fig. 4, can sufficiently it prove, NAPP and Zn2-Al-NO3-LDHs
Form stable compound.Meanwhile, the method is also the method for demarcating contained PPIX concentration in PPIX-LDHs solution.
Embodiment 6
The measure of load factor is the premise for carrying out follow-up pH release experiments.Specific method is：Weigh 1mg compound powder
End, is dispersed in DMSO, plus certain volume 1mol/L hydrochloric acid destroys hydrotalcite, then adds the 1mol/L of certain volume hydroxide
Sodium adjusts pH value, then dilutes certain multiple and surveys absorbance.According to equation：W%=nAVM/ ε m calculate load factor.Wherein
W% is the mass percent (i.e. load factor) of medicine in the composite, and n is extension rate, and A is the absorbance of measurement, and ε is mole
Absorptivity, M is the relative molecular weight of medicine, and V is the volume of liquid in cuvette, and m is the quality of weighed compound
Embodiment 7
After the meal, the pH value in stomach is between 2.0-3.0.Potassium Hydrogen Phthalate-the hydrochloride buffer for preparing pH=2.4 is molten
Liquid, weighs 5mgPPIX-LDHs and pours into 30ml cushioning liquid, be placed on magnetic stirring apparatus and be sufficiently stirred for, and control temperature to exist
37.5.DEG C time point 5min, 10min, 20min, 30min, 40min, 50min are taken, 2ml liquid is taken respectively, in 16000r/min
Rotating speed under, centrifuge 2min, take the μ l of supernatant 10 to be added in DMSO and survey ultra-violet absorption spectrum, survey Q band absorbance.Pass through above-mentioned side
The load capacity of the PPIX that method is measured in the composite, can calculate the absorbance of Q bands when PPIX all discharges in compound, enter
And calculate release percentage.As a result accompanying drawing 6 is seen, it can be seen that PPIX-LDHs is able to maintain that in the environment of pH=2.4
50min could all release.So protoporphyrin disodium (NAPP) and zinc-aluminum hydrotalcite are prepared into compound, one after each meal, in stomach
In have preferable sustained release performance, the stimulation to stomach can be effectively reduced.
Embodiment 8
Protoporphyrin can produce singlet oxygen under light illumination, and singlet oxygen has stronger cytotoxicity, so former porphin
Quinoline has phototoxicity.We test the phototoxicity of protoporphyrin-zinc-aluminum hydrotalcite compound using DPBF sonde methods.In DPBF
Literary fame claims to be 1,3- diphenyl isobenzofurans, and it is extremely unstable for singlet oxygen, in the environment that singlet oxygen is present
It can decompose rapidly.
The protoporphyrin disodium for measuring same concentrations using ultraviolet specrophotometer can make the DPBF of same concentration before and after compound
The situation of degraded.In order to reduce systematic error, additionally DPBF, (2) plus DPBF and converted only plus according to load capacity plus (1)
The zinc-aluminum hydrotalcite of same concentrations, (3) only add tri- groups of blank controls of NAPP.Experiment is carried out in dimethyl sulfoxide (DMSO) (DMSO), is used
Fluorescent lamp threw adiabatic pond irradiation, chose five time points of 30s, 60s, 90s, 120s, 150s, DPBF is in absorption maximum for measurement
The absorbance at wavelength (415nm) place.And the change for the ultra-violet absorption spectrum for passing through DPBF calculates DPBF remaining percentage.
NAPP has stronger absworption peak at DPBF maximum absorption wavelengths 415nm, can't shadow as long as NAPP is stable to light
Ring the result of experiment, it is only necessary to cut its fixation absorption value.Test result indicates that, NAPP itself can't in 150s
Degraded because of illumination, it can be concluded that at 415nm absorption peak strength change, all from DPBF.In order to intuitively
NAPP is seen before and after compound, the change that light produces singlet oxygen ability is met, using DPBF residual percentage as ordinate, to shine
Penetrate the time and make Fig. 7 for abscissa.It can be seen that NAPP and Zn2-Al-NO3After-LDHs formation compounds, singlet oxygen is produced
Ability reduces 77.9%.Therefore NAPP and Zn2-Al-NO3After-LDHs formation compounds, its light poison can be effectively reduced
Property.
Claims (6)
1. a kind of protoporphyrin-zinc-aluminum hydrotalcite compound, it is characterised in that：Its zinc-aluminum hydrotalcite surface is adsorbed in by protoporphyrin and
Into the composition of the zinc-aluminum hydrotalcite is expressed as：[Zn1-xAlx(OH)2]x+(NO3 -)x·mH2O, x value are 0.16-0.33, m values
For 0.5-2, the weight content of protoporphyrin is 0.01-50% in the protoporphyrin-zinc-aluminum hydrotalcite compound.
2. a kind of protoporphyrin-zinc-aluminum hydrotalcite compound according to claim 1, it is characterised in that：It is in aqueous
Granularity be 180-300nm.
3. a kind of preparation method of protoporphyrin as claimed in claim 1-zinc-aluminum hydrotalcite compound, it is characterised in that：It includes
Following steps：
（1）Prepare zinc-aluminum hydrotalcite：Prepare zinc ion and aluminum ions mixing salt solution, alkali lye and contain nitrate ion
The aqueous solution；Zinc ion and aluminum ions mol ratio are 2 in the mixing salt solution:1, the material of hydroxide ion in the alkali lye
Amount be 2 times of the amount sum of zinc ion and aluminium ion material；
At 15-30 DEG C of temperature, nitrogen protection and stirring condition, above-mentioned mixing salt solution and alkali lye are added dropwise to containing nitre simultaneously
In the aqueous solution of acid ion, 50-70 DEG C is warming up to after completion of dropping, aging 1-3h, aging is finished pours into reaction by reaction solution
In kettle, hydro-thermal reaction 6-12h obtains crude product at 110-130 DEG C, after the crude product is by centrifugation, washing, drying, obtains
Nitrate anion type zinc-aluminum hydrotalcite；
（2）Peel off zinc-aluminum hydrotalcite and obtain nanometer sheet gel：Above-mentioned nitrate anion type zinc-aluminum hydrotalcite is added in formamide solution,
Ultrasound is swelled 15-35min and obtains mixed liquor, and mixed liquor is then used into ultrasonic grinder ultrasound 15-35min in ice bath again,
Resulting solution forms zinc-aluminum hydrotalcite nanometer sheet gel after standing；
（3）Prepare protoporphyrin-zinc-aluminum hydrotalcite compound：Protoporphyrin disodium is dissolved in absolute ethyl alcohol, body is adjusted with NaOH solution
It is that apparent pH is 10, obtains solution A；
By step（2）Obtained zinc-aluminum hydrotalcite nanometer sheet gel is dissolved in formamide, obtains solution B；
At 15 DEG C -30 DEG C of temperature, nitrogen protection, solution A is added drop-wise in solution B, 40-50 DEG C is warming up to, continues to stir anti-
1-2h is answered, after product is by centrifugation, washing, drying process, protoporphyrin-zinc-aluminum hydrotalcite compound is produced.
4. a kind of preparation method of protoporphyrin-zinc-aluminum hydrotalcite compound according to claim 2, it is characterised in that：Institute
State step（2）, the ratio of nitrate anion type zinc-aluminum hydrotalcite and formamide is 1000 milligrams: 40-60 milliliter.
5. a kind of preparation method of protoporphyrin-zinc-aluminum hydrotalcite compound according to claim 2, it is characterised in that：Institute
State step（3）, the volume ratio of zinc-aluminum hydrotalcite nanometer sheet gel and formamide is 1: 3 in solution B.
6. protoporphyrin-zinc-aluminum hydrotalcite compound as described in one of claim 1-5 is used as the oral slow-releasing preparation of protoporphyrin
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